During sexual differentiation, an animal's body and brain develop toward a male or female pattern. According to a model established in rodents, this process is hypothesized to occur because of differential exposure to gonadal secretions. For example in males, testosterone and its more potent androgenic metabolites are important for developing the phenotypic sex of the body. This same testosterone travels to the brain where it and/or its estrogenic metabolites act to induce masculinization of brain structures. In contrast, feminine development of body and brain is believed to result from the relative absence of hormones during early development. While there is a large amount of data in vertebrates supporting the importance of hormones, additional studies are necessary because differential exposure does not adequately account for how all dimorphisms are established, particularly those in brain. One species for which this statement is especially true is the zebra finch. Males sing a courtship song that females are not normally capable of producing. In parallel with this behavioral ability, brain regions controlling singing are larger in volume and contain bigger and more numerous neurons. Little is understood about how sex differences in this system develop. In a majority of cases, hormonal manipulations result in only partial effects, or effects opposite of what would be predicted, suggesting that factors other than steroid hormones are involved. The proposed studies will test the hypothesis that neurocalcin is an important factor in the development of vertebrate neural dimorphisms. Neurocalcin is a protein belonging to a large family of calcium binding molecules. In addition to its role in calcium regulation, it has also been implicated in the pathology of several mental disorders including Alzheimer's disease and schizophrenia. Thus, results from these studies will provide data that could potentially lead to a better understanding of the progression and treatment for these conditions. Using immunocytochemistry we will characterize and determine to what extent neurocalcin protein is expressed in the brain during early development and into adulthood. Antisense-oligodeoxynucleotides will knockdown neurocalcin protein and the effects on synaptic connectivity (in vivo) and cell survival (in vitro) will be examined. Finally, we will investigate if estrogens interact with neurocalcin specifically, to alter morphology of the brain. PUBLIC HEALTH RELEVANCE: Neurocalcin is a calcium binding protein whose expression in brain is altered in individuals with Alzheimer's disease or schizophrenia. The significance of this finding is not immediately clear, but suggests that neurocalcin is involved with the onset and/or progression of these ailments. Little is known about this protein, thus this proposal will further investigate neurocalcin, providing significant data that may lead to better knowledge of the cause and treatment for these diseases.